Synthesis and pharmacological evaluation of [ 18 F]PBR316: a novel PET ligand targeting the translocator protein 18 kDa (TSPO) with low binding sensitivity to human single nucleotide polymorphism rs6971

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dc.contributor.authorMattner, Fen_AU
dc.contributor.authorKatsifis, Aen_AU
dc.contributor.authorBourdier, Ten_AU
dc.contributor.authorLoc'h, Cen_AU
dc.contributor.authorBerghofer, PJen_AU
dc.contributor.authorFookes, CJRen_AU
dc.contributor.authorHung, TTen_AU
dc.contributor.authorJackson, TWen_AU
dc.contributor.authorHenderson, Den_AU
dc.contributor.authorPham, TQen_AU
dc.contributor.authorLee, BJen_AU
dc.contributor.authorShepherd, Ren_AU
dc.contributor.authorGreguric, IDen_AU
dc.contributor.authorWyatt, NAen_AU
dc.contributor.authorLe, Ten_AU
dc.contributor.authorPoon, Jen_AU
dc.contributor.authorPower, Cen_AU
dc.contributor.authorFulham, MJen_AU
dc.date.accessioned2025-02-13T02:42:09Zen_AU
dc.date.available2025-02-13T02:42:09Zen_AU
dc.date.issued2021-04-01en_AU
dc.date.statistics2025-02-12en_AU
dc.description.abstractRadiopharmaceuticals that target the translocator protein 18 kDa (TSPO) have been investigated with positron emission tomography (PET) to study neuroinflammation, neurodegeneration and cancer. We have developed the novel, achiral, 2-phenylimidazo[1,2-a]pyridine, PBR316 that targets the translocator protein 18 kDa (TSPO) that addresses some of the limitations inherent in current TSPO ligands; namely specificity in binding, blood brain barrier permeability, metabolism and insensitivity to TSPO binding in subjects as a result of rs6971 polymorphism. PBR316 has high nanomolar affinity (4.7–6.0 nM) for the TSPO, >5000 nM for the central benzodiazepine receptor (CBR) and low sensitivity to rs6971 polymorphism with a low affinity binders (LABs) to high affinity binders (HABs) ratio of 1.5. [18F]PBR316 was prepared in 20 ± 5% radiochemical yield, >99% radiochemical purity and a molar activity of 160–400 GBq μmol−1. Biodistribution in rats showed high uptake of [18F]PBR316 in organs known to express TSPO such as heart (3.9%) and adrenal glands (7.5% ID per g) at 1 h. [18F]PBR316 entered the brain and accumulated in TSPO-expressing regions with an olfactory bulb to brain ratio of 3 at 15 min and 7 at 4 h. Radioactivity was blocked by PK11195 and Ro 5-4864 but not Flumazenil. Metabolite analysis showed that radioactivity in adrenal glands and the brain was predominantly due to the intact radiotracer. PET–CT studies in mouse-bearing prostate tumour xenografts indicated biodistribution similar to rats with radioactivity in the tumour increasing with time. [18F]PBR316 shows in vitro binding that is insensitive to human polymorphism and has specific and selective in vivo binding to the TSPO. [18F]PBR316 is suitable for further biological and clinical studies. © Royal Society of Chemistry 2025.en_AU
dc.description.sponsorshipThis project was funded by the Department of Molecular Imaging, Royal Prince Alfred Hospital, ANSTO, Biological Resources Laboratory (UNSW) and the Prostate Cancer Foundation of Australia, Grant NCG 5012.en_AU
dc.format.mediumElectronic-eCollectionen_AU
dc.identifier.citationMattner, F., Katsifis, A., Bourdier, T., Loc'h, C., Berghofer, P., Fookes, C., Hung, T.-T., Jackson, T., Henderson, D., Pham, T., Lee, B. J., Shepherd, R., Greguric, I., Wyatt, N., Le, T., Poon, J., Power, C., & Fulham, M. (2021). Synthesis and pharmacological evaluation of [18F]PBR316: a novel PET ligand targeting the translocator protein 18 kDa (TSPO) with low binding sensitivity to human single nucleotide polymorphism rs6971. RSC Medicinal Chemistry, 12(7), 1207-1221. doi:10.1039/D1MD00035Gen_AU
dc.identifier.issn2040-2503en_AU
dc.identifier.issn2632-8682en_AU
dc.identifier.issue7en_AU
dc.identifier.journaltitleRSC Medicinal Chemistryen_AU
dc.identifier.pagination1207-1221en_AU
dc.identifier.urihttps://doi.org/10.1039/d1md00035gen_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15978en_AU
dc.identifier.volume12en_AU
dc.languageEnglishen_AU
dc.language.isoenen_AU
dc.publisherRoyal Society of Chemistry (RSC)en_AU
dc.subjectSynthesisen_AU
dc.subjectPharmacologyen_AU
dc.subjectProteinsen_AU
dc.subjectNucleotidesen_AU
dc.subjectBrainen_AU
dc.subjectPyridineen_AU
dc.subjectRadiopharmaceuticalsen_AU
dc.subjectTranslocationen_AU
dc.subjectPositron computed tomographyen_AU
dc.subjectBlooden_AU
dc.subjectRatsen_AU
dc.subjectReceptorsen_AU
dc.titleSynthesis and pharmacological evaluation of [ 18 F]PBR316: a novel PET ligand targeting the translocator protein 18 kDa (TSPO) with low binding sensitivity to human single nucleotide polymorphism rs6971en_AU
dc.typeJournal Articleen_AU
dcterms.dateAccepted2021-03-15en_AU
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